Carlo Silipo

Use of the hydrogen bond potential function in a comparative molecular field analysis (CoMFA) on a set of benzodiazepines

SummaryThe results of the GRID-Comparative Molecular Field Analysis (CoMFA) were compared with those of the SYBYL-CoMFA in a study of benzodiazepines. The results demonstrate that the hydrogen bonding function using the GRID H2O probe in a CoMFA can successfully describe the hydrophobic effects of substituents without any bias or preconcept of their effects in the development.

Effects of variable selection on CoMFA coefficient contour maps in a set of triazines inhibiting DHFR

SummaryAn example of a CoMFA study is described with the aim to discuss one of the major problems of this 3D QSAR method: lack of variable selection. It is shown that the use of nonrelevant energy parameters might produce CoMFA contour maps which poorly reflect the actual nature of the binding site and are in part statistical artefacts. The data set employed in our analysis comparises triazine inhibitors of dihydrofolate reductase (DHFR), isolated from chicken liver, which have already been the object of a QSAR study by other authors. Since three-dimensional structures of triazine-DHFR complexes are known, it was possible not only to reduce ambiguities in the superimposition of the ligands, but also to compare the resulting CoMFA contour maps with the enzyme active site.

Quantitative structure-activity relationships in a set of thiazolidin-4-ones acting as H1-histamine antagonists

A series of 2-(3- and 4-substituted phenyl)-3-[3-(N, N-dimethyl-amino)propyl]-1,3-thiazolidin-4-ones acting as H1-antihistaminics was investigated with a combined Hansch-CoMFA approach. The substituents at the 3- and 4-positions of the phenyl ring have been described through steric, electronic and hydrophobic parameters and correlated with pA2 values. The obtained quantitative models suggest that affinity to the receptor is promoted by hydrophobic and small 4-substituents and by 3- and 4-substituents generating a positive electrostatic potential towards a complementary receptor region.

Solid-state structure and conformation of (Z)-2-(phenylbenzylidene)-3-quinuclidinone, an intermediate in the synthesis of quinuclidine derivatives

Abstract(Z)-2-(2-phenylbenzylidene)-3-quinuclidinone, C20H19NO,Mr=300.47D crystallizes in the monoclinicP21/c space group witha = 6.9809(2) Å,b=19.0523(2) Å,c = 11.7733(1) Å,β=100.92(2)°,V=1537.5(3) Å3,Z=4,Dc = 1.298 g/cm3,Dx=1.29 g/cm3 (flotation). Diffractometric data, using CuKα radiation,λ=1.54178 Å, were collected on plate-like crystals. The structure, solved by direct methods was refined to a final R value of 0.037 for the 2645 observed reflections withFo>3.0σ(Fo). The molecule shows a trans conformation around the double bond. The quinuclidine and the diphenyl moieties present deformations in their geometric and conformational parameters due to the need of releasing intramolecular strains and/or nonbonded interactions.

Correlation analysis of ligand interactions with cycloamyloses

Abstract Correlation equations have been developed for the hydrolysis of phenyl acetates by cycloamyloses. These quantitative structure-activity relationships (QSAR) for the enzyme-like activity of the polysaccharides are then compared with QSAR for synthetic “mini-enzymes” which have been studied in several laboratories. The physicochemical parameters determining activity of these “pseudo-enzymes” are similar to those determining activity with real enzymes.